Beneficial effects of potassium cardioplegia during intermittent aortic cross-clamping and reperfusion

Aortic cross-clamping is an essential adjunct to a variety of cardiac surgical procedures requiring a quiet flaccid heart and avoidance of systemic air embolism. The consequences of excluding the heart from perfusion, oxygen, and substrate are time dependent and lead ultimately to irreversible damage of the myocardium. The goal of complete preservation of myocardial function and metabolism during ischemia has not been realized even with the best clinically applicable techniques. The present study was designed to evaluate the effects of sequential aortic cross-clamping interrupted by reperfusion similar to that used in clinical practice. The advantages of induced cardiac arrest with potassium chloride solution at the onset of aortic cross-clamping were assessed in a second group of animals. A total of 27 mongrel dogs supported by normothermic cardiopulmonary bypass was subjected to four aortic cross-clamp periods interrupted by 5-min reper-fusion periods. The study included an evaluation of left ventricular performance using an isovolumic balloon technique and an assessment of myocardial metabolism using “stop-freeze” biopsies and biochemical assay for ATP, ADP, AMP, and creatine phosphate. The data demonstrate that repeated induction of ischemic arrest results in profound depletion of adenine nucleo-tides and severe depression of contractility. Using potassium-induced cardiac arrest, normal contractile function is preserved along with conservation of adenine nucleo-tides, suggesting that even at normothermia, preservation of the heart during ischemia can be achieved.     

Verapamil potassium cardioplegia and cardiac conduction

This clinical study analyzes the effect of potassium cardioplegic solution containing verapamil hydrochloride (1 mg/L) on cardiac conduction after release of the aortic cross-clamp and throughout recovery. Fifty consecutive patients undergoing open-heart operation were studied as a unit for postoperative conduction abnormalities. They were also analyzed in groups based on spontaneous ventricular conversion to regular rhythm (54%) and the need for single DC cardioversion (32%), or multiple DC cardioversions (14%). Results showed that spontaneous ventricular conversion had no relationship to aortic cross-clamp time and that DC cardioversion using 10 Ws had no detrimental effects on the myocardium or incidence of conduction abnormalities. The need for transient intraoperative pacing was lowest with spontaneous ventricular conversion, but not statistically different from single or multiple DC cardioversions. Only 3 patients (6%) required pacing in the intensive care unit. The incidence of postoperative atrial and ventricular arrhythmias was similar in all groups, and no deaths or episodes of malignant ventricular arrhythmias occurred. This study concludes that verapamil potassium cardioplegia is associated with excellent myocardial protection and a high incidence of transient intraoperative dysfunction of the atrioventricular node (70%) but a low incidence of postoperative pacing. Benign postoperative arrhythmias occur, but at hospital discharge, few conduction abnormalities (10%) persist.     

Lactate release during reperfusion predicts low cardiac output syndrome after coronary bypass surgery

Background. Cardioplegic arrest induces anaerobic myocardial metabolism with a net production of lactate from glycolysis. However, persistent lactate release during reperfusion suggests a delayed recovery of normal aerobic metabolism and may lead to depressed myocardial function necessitating inotropic or intraaortic balloon pump support (low output syndrome [LOS]). We examined the relation between perioperative myocardial metabolism and postoperative clinical outcomes in patients undergoing isolated coronary artery bypass surgery (CABG).

Methods. We reviewed 623 patients who were enrolled in clinical studies evaluating perioperative myocardial metabolism between 1983 and 1996. Arterial and coronary sinus blood samples were obtained intraoperatively to assess myocardial metabolism. Clinical data regarding patient demographics and postoperative outcomes were prospectively collected and entered into our institutional database.

Results. Low output syndrome developed in 36 patients (5.8%). Myocardial lactate release was higher in these patients compared with those who did not develop postoperative LOS. Advanced age and poor preoperative left ventricular function were independent predictors of lactate release during reperfusion. Persistent lactate release after 5 minutes of reperfusion was the only independent predictor of postoperative LOS in this low-risk population.

Conclusions. Persistent lactate release during reperfusion occurs in a significant proportion of low-risk patients undergoing isolated CABG and is an independent predictor of postoperative low cardiac output syndrome. Persistent lactate release during reperfusion suggests a delayed recovery of aerobic myocardial metabolism and may be related to intraoperative misadventure or inadequate myocardial protection. Myocardial lactate release may be useful as an alternative end-point in clinical trials evaluating perioperative myocardial protection.     

Intracellular calcium increasing at the beginning of reperfusion assists the early recovery of myocardial contractility after diltiazem cardioplegia

Objectives: We investigated the ability of diltiazem to prevent myocardial injury by assessing heart function and intracellular calcium concentrations before and after ischemia-reperfusion. Method: Isolated rat hearts underwent cardioplegia using the Langendorff perfusion model and were subjected to normothermic global ischemia for 60 minutes. The recovery rates for the heart function (heart rate, coronary flow, left ventricular systolic pressure) after reperfusion were monitored, and the intracellular Ca concentration was measured during ischemia and during the following reperfusion. Experimental groups were divided into three groups according to the diltiazem concentration used in the cardioplegic solution (potassium 20 mmol/l in Ringer's solution): (1) Group A: diltiazem 2.5 mg/l; (2) Group B: diltiazem 5 mg/l; and (3) Group C: no diltiazem. Results: Intracellular calcium concentration increased in all 3 groups during ischemia, but was significantly lower in Group B compared to either Group A or Group C. The heart function was significantly higher for Group A than for Group B or Group C. The hearts in Group B displayed markedly poor recovery in contractility and in heart rate. Conclusions: Generally, a decrease in intracellular Ca concentration improves the heart function during ischemia and after reperfusion. However, this study showed that some increase in intracellular Ca at the beginning of reperfusion assisted the contractility of rat heart.     

Avoidance of reperfusion injury after cardioplegia.

Myocardial damage incurred by ischaemia appears during and seems to be accelerated by reperfusion, which restores recoverable cells and disrupts badly damaged ones. Vicious cycles of oedema, calcium accumulation, acidosis, oxygen toxicity, fibrillation and air and platelet emboli contribute to the reperfusion injury. The philosophy of cool low-pressure reperfusion gradually restoring temperature and pressure to normal is here contrasted experimentally with that of immediate normothermic, normotensive perfusion after 90 minutes of ischaemic cool, cardioplegic arrest. The preparation was a canine heart which was treated according to the usual clinical protocol except that one group was reperfused at normal temperature and pressure, and the other group started reperfusion cool and at a low pressure and over the next 10 minutes pressure and temperature were restored to normal. Isovolumic ventricular function studies were done before ischaemia and after recovery and showed statistically significant differences between the groups in favour of the immediate restoration of normal temperature and pressure of perfusion. Contractile velocity and systolic pressure showed very highly significant (p = less than 0.005) differences, wall stress significant (p = less than 0.025) and compliance not significant differences between the groups. Reperfusion with optimal conditions may prevent "vicious cycle" changes in ischaemically damaged but recoverable myocardium. We have shown that a step in this direction is reperfusion with blood at normal temperature and pressure rather than initially at lowered temperature and pressure.     

Rod-like intramitochondrial inclusions after hypothermic chemical cardioplegia during cardiac operations

Rod-like intramitochondrial inclusions in the myocardial cells were observed after hypothermic chemical cardioplegia in three out of 20 patients who underwent coronary bypass operations. They were not seen in another group of 20 patients who underwent an aortic valve replacement operation in whom only topical cooling was used for myocardial protection. The occurrence of rod-like intramitochondrial inclusions could not be correlated with other signs of ischemic myocardial injury. X-ray microanalysis did not reveal any inorganic substance in the intramitochondrial inclusions. Therefore, we believe that their occurrence was not related to the calcium paradox phenomenon, a feared complication of cardiac operations.     

The effects of propofol on cardiac function after 4 hours of cold cardioplegia and reperfusion

OBJECTIVE: To examine whether propofol protects against postischemic myocardial dysfunction and apoptosis during reperfusion after prolonged cold ischemia in isolated rat hearts. DESIGN: A prospective, randomized, controlled study. SETTING: A university laboratory. PARTICIPANTS: Animals. INTERVENTIONS: The isolated hearts of 40 Sprague-Dawley male rats were perfused with modified Krebs-Hennseleit solution for 15 minutes for a stabilization period and 15 minutes for a perfusion period and then underwent 4 hours of global cold ischemia followed by 60 minutes of reperfusion. Four groups were studied (n = 10 for each group). Ten hearts served as an untreated control group. Propofol (2 micromol/L) treatment was performed only before ischemia in the PRE group, only during reperfusion in the POST group, and both before and after ischemia in the ALL group. MEASUREMENTS AND MAIN RESULTS: Infusion of propofol during reperfusion improved recovery of left ventricular-developed pressure (LVDP) from 61.2% +/- 8.5% (control) to 86.3% +/- 12.1% (POST) and 74.9% +/- 13.2% (ALL, both p < 0.05), whereas preischemic infusion of propofol (64.3% +/- 9.7%, PRE) did not improve recovery of LVDP. Infusion of propofol during reperfusion significantly reduced the number of apoptotic cells and led to a smaller infarct size than control and PRE groups (p < 0.05, respectively). CONCLUSIONS: Propofol infusion during the reperfusion period produced a cardioprotective effect and inhibited apoptosis of cardiomyocytes in the ischemia-reperfusion model, with prolonged cold ischemia, in isolated rat hearts.     

Coronary blood flow and myocardial metabolism during reperfusion after hypothermic cardioplegia in the dog

There have been many studies of reperfusion injury after normothermic ischemia. However, there have been few clinically relevant studies on the nature and time course of recovery of the myocardium during reperfusion after hypothermic cardioplegia. We studied reperfusion in the isolated dog heart supported by another dog. After 2 h of cardioplegic arrest at 20 degrees C, 11 normal hearts were reperfused for 30 min at optimal coronary pressures (60-100 mm Hg mean). The following events occurred: rapid rewarming, a transient hyperemia followed by a rapid return of both coronary blood flow and myocardial oxygen consumption to normal, washout of lactate, recovery of contractility and a slight decline in ATP. Most of these events occurred during the first 15 min of reperfusion. We concluded that, in normal hearts which are well protected during hypothermic cardioplegia, reperfusion at optimal coronary pressure results in recovery of the myocardium within 15 min, with the exception of recovery of ATP levels.     

Non-depolarizing cardioplegia activates Ca-ATPase in sarcoplasmic reticulum after reperfusion

Objectives: Depolarizing cardioplegia is the most common method for myocardial preservation in cardiac operations. However, depolarizing cardioplegia causes depolarization of the membrane potential by extracellular hyperkalemia, resulting in depletion of energy stores and calcium overload. This study examined the hypothesis that non-depolarizing cardioplegia would provide superior protection compared with depolarizing cardioplegia. Methods: In an isolated rat heart Langendorff model, hearts were perfused for 10 min with St. Thomas' Hospital cardioplegic solution (Group I: n=20), St. Thomas' Hospital cardioplegic solution+Lidocaine 1 mM (Group II: n=20) or non-depolarizing cardioplegia (Group III: n=20). The hearts then were subjected to 60 min of normothermic global ischemia, after which they were perfused with Krebs–Henseleit buffer at 37 °C for 30 min. The percent recovery of functional data, myocardial cyclic AMP contents, and myocardial cyclic GMP contents were recorded at each time point (base, after the administration of cardioplegia, after global ischemia, and after 30 min of reperfusion). Ca²⁺-ATPase in sarcoplasmic reticulum was measured at pre-ischemia and 30 min of reperfusion. Results: The percent recovery of developed pressure and ±dp/dt were significantly higher in Group III than in other groups. Myocardial cyclic AMP and GMP contents were elevated after reperfusion in all groups. However, in Group III, myocardial cyclic AMP contents after 30 min of reperfusion were significantly higher than in other groups (Group III: 14.7±1.6 vs. Group I: 8.7±1.0, Group II: 8.3±0.2 pmol/mg dry weight, P=0.05) but not cGMP. The sarcoplasmic reticulum Ca²⁺-ATPase activities at 30 min of reperfusion significantly increased in Group III compared with Groups II and I (Group III: 70.3±3.6 vs. Group I: 46.8±3.4, Group II: 53.9±6.1 μmol Pi/mg per h, P=0.025 and P=0.030). Conclusions: Non-depolarizing cardioplegia induced the activity of Ca²⁺-ATPase in sarcoplasmic reticulum after reperfusion. The activity would be increased by the cyclic AMP pathway. These findings suggested that non-depolarizing cardioplegia prevented calcium overload after reperfusion, especially decreased cytosolic calcium during the diastolic phase.     

Assessment of prostacyclin and thromboxane A2 release during reperfusion after global ischemia induced by crystalloid cardioplegia--comparison between warm and cold ischemia

The metabolites of prostacyclin (PGI2) and thromboxane A2 (TxA2), 6-keto-PGF1 alpha and thromboxane B2 (TxB2), were investigated during reperfusion (RP) following warm (37 degrees C, 60 min, n = 9) or cold (15 degrees C, 120 min, n = 11) ischemia induced by cold (4 degrees C) or normothermic (30 degrees C) K+ cardioplegia (CP) in isolated canine hearts subjected to global ischemia and RP. 6-Keto-PGF1 alpha flux was significantly higher (p less than 0.025) in the warm group at 1, 5, and 10 min of RP (4,202 +/- 1,412, 2,475 +/- 1,875, and 1,255 +/- 633 pg/g.min, mean +/- SD) compared to those in the cold group (1,504 +/- 1,245, 434 +/- 641, and 370 +/- 329 pg/g.min). TxB2 flux was small in amount compared to 6-keto-PGF1 alpha in both groups. Regarding the coronary hemodynamics, the cold group alone showed statistically significant relationships of coronary sinus blood flow to TxB2 level and TxB2/6-keto-PGF1 alpha ratio in coronary sinus blood. Also, coronary vascular resistance showed linear relations to these two parameters of the metabolites. In a supplementary experiment only with cold ischemia for 180 min, 6-keto-PGF1 alpha was released at each coronary flush-out by CP and the incremental amount showed a gradual increase during ischemia. These results indicated that significant production and release of PGI2 occurred during ischemia and RP following CP arrest and these related to the degree of myocardial damage while the response of TxA2 seemed less significant. The role of PGI2 release during RP following cardioplegic arrest was discussed.     

Measurement of potassium absorption during hypokinesia in potassium supplemented and unsupplemented healthy subjects

Measuring potassium (K⁺) absorption, and K⁺ levels in plasma, urine and feces during and after hypokinesia (HK) and K⁺ supplementation, the aim of this study was to determine if prolonged HK could depress K⁺ deposition significantly more with or without K⁺ supplementation. Studies were conducted during 30-days pre-HK, 364-days HK and 30-days post-HK. Forty male healthy volunteers 24.2 ± 5.5 years of age were chosen as subjects. They were equally divided in four groups: unsupplemented active control subjects (UACS), unsupplemented hypokinetic subjects (UHKS), supplemented active control subjects (SACS), and supplemented hypokinetic subjects (SHKS). Hypokinetic subjects were walking average distances of 0.5 ± 0.2 km day^–1. Active control subjects were running average distances of 5.8 ± 1.2 km day^–1. Both SHKS and SACS consumed daily 2.17 mEq elemental potassium per kg body weight. Potassium absorption, fecal and urinary K⁺excretion, sodium (Na⁺) loss, plasma K⁺ and Na⁺ level and plasma aldosterone (PA) level did not change in SACS and UACS compared with their pre-HK values. During HK, K⁺ absorption decreased significantly (P < 0.05) with time, and fecal and urinary K⁺ loss, urinary Na⁺ loss, plasma K⁺ and Na⁺ levels and PA level increased significantly (P < 0.05) with time in SHKS and UHKS compared with their pre-HK values and their respective active controls (SACS and UACS). During initial 15-days of post-HK, K⁺ absorption increased significantly (P < 0.05), fecal and urinary K⁺ excretion, urinary Na⁺ excretion and plasma K⁺ and Na⁺ levels and PA level decreased significantly (P < 0.05) in hypokinetic compared with active control subjects; by the 30th day they approached the control levels. During HK and post-HK, K⁺ absorption, fecal and urinary K⁺ losses, urinary Na⁺ excretion, plasma K⁺ and Na⁺ levels and PA level, changed significantly (P < 0.05) more in SHKS than UHKS. Decreased K⁺ losses during post-HK showed K⁺ depletion during HK. Decreased K⁺ absorption with K⁺depletion during HK showed decreased K⁺ deposition. The greater K⁺ changes in SHKS than UHKS, during HK and post-HK, demonstrated that K⁺ deposition decreased more with than without K⁺ supplementation. It was concluded that dissociation between K⁺ absorption and K⁺ depletion showed decreased K⁺ deposition as the main mechanism for K⁺ depletion during HK.     

Effects of diltiazem cardioplegia on global function, segmental contractility, and the area of necrosis after acute coronary artery occlusion and surgical reperfusion

We investigated the effects of diltiazem cardioplegia on myocardial function and infarct size in the region of the left anterior descending artery after acute occlusion and reperfusion during cardiopulmonary bypass. Sheep (30 kg) were subjected to 1 hour of regional myocardial ischemia by occlusion of the left anterior descending artery and assigned to a control (n = 8) or experimental group (n = 5). Control animals were placed on cardiopulmonary bypass and the heart arrested with potassium cardioplegia. The left anterior descending artery was released and two additional doses of 100 ml of cardioplegic solution were infused during the total cross-clamp time of 30 minutes. The animals were then weaned from bypass after 1 hour and beating, working reperfusion maintained for an additional 4 hours. The experimental group followed the same protocol except that the cardioplegic solution contained diltiazem (1.4 mg/L). Segmental myocardial function was determined by pairs of ultrasonic crystals in the area at risk, control segment, and minor axis. Global contractility was determined from maximum derivative of left ventricular pressure and cardiac output. The area at risk was determined by injecting monastral blue dye into the left atrium with the left anterior descending artery briefly reoccluded, and the area of necrosis was determined by measuring with a planimeter non-triphenyltetrazolium chloride stained areas in the sectioned left ventricle. After 5 hours of reperfusion, not only did the diltiazem group demonstrate better global contractility as defined by the derivative of left ventricular pressure (1853 +/- 292 versus 979 +/- 191, p = 0.05) but, in addition, the systolic shortening in the ischemic area improved significantly when compared with the control group (9.4 +/- 4 versus 2.13 +/- 0.77, p = 0.05). The group receiving diltiazem cardioplegia had an area of necrosis to area at risk ratio of 31.4% +/- 3%, which was significantly better than this ratio in the control group of 60.75% +/- 7% (p = 0.01). Diltiazem cardioplegia results in improved global and segmental contractility and limits the infarct size after occlusion of the left anterior descending artery and surgical reperfusion.     

Intramyocardial electrical and metabolic activity during hypothermia and potassium cardioplegia

Hypothermic potassium cardioplegia is widely used to reduce myocardial metabolism as a means of myocardial protection. To investigate the efficacy of intramyocardial electrical activity as an indicator of myocardial metabolism, 12 dogs were placed on cardiopulmonary bypass and myocardial oxygen consumption, partial pressure of carbon dioxide (PCO2) in the coronary sinus, myocardial temperature, and intramyocardial and surface electrocardiograms were measured. The hearts were fibrillated and cooled to 15 degrees C. In Group 1 (6 dogs), potassium cardioplegia was given at 15 degrees C. In Group 2 (6 dogs), it was given at 25 degrees C. Maximum coronary sinus PCO2 and oxygen consumption occurred at 36 degrees C and gradually decreased, but there was still evidence of metabolic activity and intramyocardial electrical activity at 15 degrees C. When cardioplegia was given at 15 degrees C, all electrical activity ceased and there was a further significant reduction in metabolic activity (coronary sinus PCO2 and oxygen consumption). In Group 2 similar findings were found at 25 degrees C, and there was no further reduction in metabolic activity at 15 degrees C. These data indicate that: (1) myocardial metabolic activity is lowest when there is electrical quiescence as measured with an intramyocardial electrode; (2) potassium arrest and hypothermia are both necessary to achieve electrical quiescence; and (3) in the potassium-arrested heart, lowering temperature from 25 degrees to 15 degrees C does not result in a further reduction of metabolic activity.     

Preservation of myocardial function and biochemistry after blood and oxygenated crystalloid cardioplegia during cardiac arrest

We compared the ability of blood cardioplegia and oxygenated crystalloid cardioplegic solutions to maintain regional left ventricle contractility and adenosine triphosphate levels after cardiopulmonary bypass. Ten baboons were subjected to 90-minute cardiopulmonary bypass conducted at 28 degrees C. Hemodynamic measurements were made before and after the bypass procedure, and biopsies for high-energy phosphate determinations were performed at different time intervals during and after bypass. The results showed improved maintenance of myocardial contractility (measured with the regional end-systolic pressure-length relationship) with the oxygenated crystalloid solution. Expressed as a percentage of values before bypass, contractility after bypass averaged 81.69% +/- 4.81% and 80.47% +/- 10.05%, respectively, after 10 and 20 minutes using the oxygenated crystalloid cardioplegia. For blood cardioplegia, the corresponding values were 71.9% +/- 8.73% and 64.99% +/- 8.60% (mean +/- standard error of the mean). The 10- and 20-minute postbypass values between the two groups differed significantly (t test, Welch modification: p = 0.0464 and p = 0.0342). Myocardial adenosine triphosphate level was higher immediately after induction of cardiac arrest when blood cardioplegia was used (blood cardioplegia, 6.82 mol.g wet wt-1; crystalloid cardioplegia, 4.95 mol.g wet wt-1; p = 0.0314), but values subsequently equalized.